CHARACTERIZATION OF NEUROPROTECTIVE EFFECTS MEDIATED BY PROLYL ENDOPEPTIDASE-INHIBITORY COMPOUNDS FOR THE TREATMENT OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The deposition of abnormally folded alpha-synuclein (aSyn) protein in Lewy bodies is thought to contribute to the pathogenesis of PD. Furthermore, mitochondrial dysfunction leading to oxidative stress is implicated in neuronal cell death, and dopaminergic neurons are specifically vulnerable to oxidative stress. In addition to motor symptoms, non-motor symptoms such as depression develop early in disease progression. There is currently no treatment to halt neurodegeneration in PD, but reduction of aSyn pathology and oxidative stress are promising therapeutic targets. Here, we investigated whether a prolyl endopeptidase (PREP) inhibitor is neuroprotective in in vivo and in vitro models of aSyn pathology. Mice overexpressing human wild-type aSyn (Thy1-aSyn, line 61) were used to establish primary neuronal cultures on multi microelectrode arrays (MEA) to measure neuronal firing and viability. Oxidative stress, induced by a stable peroxide, reduced neuronal firing, which was alleviated by adding the PREP inhibitor, suggesting neuroprotective effects. These findings were further supported by an in vivo study using Thy1-aSyn transgenic mice. Treated for one month via intraperitoneal implanted osmotic minipump loaded with the PREP inhibitor, transgenic mice exhibited less progression of motor deficits, enhanced short-term memory, and reduced hyperactivity. Importantly, the compound reduced aSyn pathology and microglia reactivity in the substantia nigra. These results indicate that PREP-inhibitors hold promise as neuroprotective agents in PD, warranting further investigation to validate and expand upon these initial findings.